Saturday, 29 April 2017

Cancer Research Uk Skin Cancer

good afternoon, or goodmorning or good evening, depending on where you'relistening from. i'm dr. john iskander, on behalfof cdc i'd like to welcome you to april's public health grandrounds. continuing education credits forpublic health grand rounds are available for physicians,nurses, pharmacists, health educators and other healthprofessionals. please see more at the grandrounds website. grand rounds is also availableon all of your favorite web and

social media sites.we have a featured video on youtube called "beyond thedata" which is posted shortly after the session.this month's segments features my interview with deputy surgeongeneral boris lushniak. we're live tweeting, ususe #cdcgrandrounds for all your tweeting needs.for those of you interested in related topics, many of thepeople involved in putting this session were also involved inwriting up an article recently published in the mmwr on thefuture of cancer screening.

please look for that online.today's speakers include not only the current deputy andformer acting surgeon general but an actual surgeon.i think that's a first. it's our pleasure and privilegeto work closely with our speakers to bring you thesesessions each month. i commonly introduce ourspeakers as public health heroes.in recognition of the coming may summer action movie season,you'll see that we have actually some superheroes in today'ssession as well.

we've partnered with the cdcpublic health library and information center to featurescientific articles relevant to the session, the full listis at cdc.gov/scienceclips.here is a preview of upcoming grand round sessions, pleasejoin us live or on the web at your convenience.it's now my pleasure to introduce admiral robin ikeda,deputy director for noncommunicable diseases, injuryand environmental health. thank you and good afternoon.we're delighted you could join

us this afternoon.skin cancer is one of the most commonly diagnosed cancers inthe united states, yet most cases are preventable.while rates of other cancers are decreasing, the rates of skincancer are increasing, creating a serious public health concernthat we cannot ignore. melanoma is one of the mostcommon cancers among u.s. adolescents and young adults.although those with lighter skin are more at risk, anyone can getskin cancer, and it can be serious, disfiguring and evendeadly.

ultraviolet or uv radiationis the most preventable cause of skin cancer.the most common types are strongly associated withexposure to uv radiation. tan skin is a sign of damagedskin, not health. when people tan or get sunburned, they increase the risk of getting skin cancer.there is no evidence that indoor tanning is safer than tanningoutdoors, or provides any protection from further sunexposure. indoor tan something riskybehavior, yet one out of every

three young white high schoolgirls reported indoor tanning in 2012.the surgeon general's call to action with a prevent skincancer was released last july and creates a plan for multiplesectors to take an active role in preventing skin cancer.as you heard, we're honored today to have the u.s. deputysurgeon general boris lushniak. schools and early learningcenters, colleges and universities, employers andemployee, health care systems, insurers and clinicians can alltake an active role in

protecting communities andindividuals from uv exposure. today you'll hear case studiesand examples of these policies and personal actions in thesession. today we'll hear aboutinnovative efforts at the federal, state and local levelthat are raising awareness about the increasing tide of skincancers. these efforts include bringingpartners together across federal agencies and in communities toaddress risk factors for skin cancer, intervene using proveneffective tools and accelerate

their progress over time.two of our speakers today come from heavily sun exposedstates -- arizona and texas, that recognize the need to takeaction against skin cancer at the population level.to reduce skin cancers in the population, people must get theinformation they need to make informed choices about sunprotection, policies must support these efforts, and youthmust be protected from the harms of indoor tanning.achieving these goals will not be a small task.it will require dedication,

ingenuity, skill, and aconcerted efforts of many partners in prevention acrossmany different sectors. many of these partners arealready involved but greater cooperationand support are needed to increase their reach of theseefforts. we must act with urgency to stopthe ever-increasing incidence of skin cancers in the unitedstates. thank you.[ applause ] thank you, admiral ikeda.our first speaker is meg watson.

skin cancer begins in thecells of the skin. there are three most commontypes of skin cancer, and in order of incidence those arebasal cell carcinomas, squamous cell carcinomas and melanomas.basal cell carcinomas alone are thought to be the most commontype of cancer. melanomas originate in thecells that make melanin, and it's the most deadly of thethree common types of skin cancer.skin cancer is associated with a significant public healthburden.

estimates for medical extendtours show nearly 5 million skin cancers are treated in the u.s.each year. about 65,000 malignant melanomaswere diagnosed in 2011 and about 9,000 deaths due to the diseasein that year. there are also about 3,000deaths due to non-melanoma skin cancers each year, includingsome deaths from squamous melanomas and other skin cancer.they do not collect information on the more common so incidencewill be presented here. this slide shows invasivemelanoma incidence data from

the national cancer institutesprogram. incidents from melanoma isincreasing since at least the 1970s.incidence rates are higher overall for males, but have beenincreasing consistently for both sexes.we've seen overall incidence roughly triple over the last twogenerations with an average annual percentage increase ofabout 3% each year. this slide shows aggregated dataon invasive melanoma incidence over a five-yearperiod from cdc's national

program of cancer registries andnci's s.e.e.r. program which covers the united states.it starts at about age 50, however rates among adolescentsand young adults are higher among females than males.melanoma is the second most common cancer among women intheir 20s, likely related to intentional tanning eitheroutdoors or indoors. you'll hear much more about thisproblem and how it's being addressed by subsequentspeakers. and skin cancer is costly.treatment for skin cancer costs

$8.1 billion each year in theunited states, and annual costs more than doubled between theperiods 2002 to 2006, and 2007 to 2011.genetics has a strong effect on skin cancer risk.having light hair and eyes, fair skin, skin that burns, orfreckles or certain types or a large number of moles increasesthe risk of skin cancer as does having a family or a previouspersonal history of skin cancer. although those with lighter skinare at higher risk, people with darker skin may often bediagnosed later, making it more

difficult to treat.this slide again shows data from nci and cdc combined and showsmelanoma rates by race and hispanic ethnicity.non-his panning whites have 25 times compared to blacks and sixtimes the rate of hispanics. rates are higher among males inall ethnicities except for blacks for which statistics arenot significant. these differences are primarilyrelated to differences in skin type.melanin gives skin its color and protective against uv radiationso darker skin has more

protection.it's important to remember there's wide variability in skintypes and sun sensitivity within racial and ethnic groups.despite the importance of skin type and non-modifiable riskfactors, public health efforts focus on uv radiation exposurebecause it's the most preventable cause of skincancer. between 65% and 90% of skincancers are thought to be caused at least in part by uvradiation. uv from sunlight is the mostcommon source of exposure but

some people are exposed toartificial sources of uv from cosmetic indoor tanning, medicaltreatment or less commonly occupational exposures.uv damages the skin cell's dna. the lag time between exposure touv and development of cancer is thought to be about 10 to 20years but in some cases this time period appears to be muchshorter. and uv varies by wavelength.uva penetrates more deeply than uvb and both can cause cancer.the term broad spectrum protection means products suchas sunscreen protect against

both types of uv rays.tans and sunburns are reactions to damage from uv.although tanning provides a small amount of protectionagainst future burns, it also indicates that damage hasoccurred. sunburns indicate cell deathoccurred. national surveys and researchstudies, sunburns are used as indicators of uv exposurebecause they take into account individual sensitivity to uvrather than just exposure time. rates of sunburn remain highwith about 37% of americans

reporting getting burned everyyear. and among those who reportburning, many get burned frequently defined here as fouror more times in the past year. uv damage adds up over time.sunburns and overexposure in childhood and in adulthood canincrease risk. it's not surprising that, withhigh sunburn rates there's room for improvement andsun protection. although 70% of adults reportalways protecting themselves from the sun, when outdoors formore than an hour on a sunny day

a closer look at methods ofprotection tells a different story.use of each individual method of protection is quite a bit lowerparticularly using a wide brimmed hat or long sleevedshirt. protection differs by gender.with women primarily seeking shade or using sunscreen and menwearing long clothing to the ankles as their most commonmethod of protection. national survey asking highschool students about sunscreen found that only 10% of studentsreported wearing sunscreen when

outdoors on a sunny day for morethan an hour, that's 13% of females and only 7% of males.unfortunately this is not the only behavior that puts youth atrisk from skin cancer. indoor tanning exposes users tointense uv to tan the skin for cosmetic purposes.this intense uv increases the risk of skin cancer.one study estimated that about 400,000 cases of skin cancer inthe united states could be caused by indoor tanning eachyear, including over 6,000 melanomas.indoor tan something common

mopping some groups.tanning rates are highest among non-hispanic white women andpeak age 16 to 25. almost one in three of thesewomen report indoor tanning in the past year.the food and drug administration warns against indoor tanning bypeople younger than age 18 and 11 states currently prohibittanning by minors. recent estimates suggest about1.6 million high school students younger than age 18 are tanningin the u.s. each year. so what works to prevent skincancer?

reducing overexposure to uvreduces rates of skin cancer in the population but how do we getthere? because of the long lag time andlarge populations required to detect cancer outcomeseffectiveness is usually measured by reductions insunburn or indoor tanning and increases in sun protection.based on the outcomes the community guide recommendedseveral interventions. multi-component community wideinterventions are defined as at least two interventionsimplemented in at least two

different types of settings, sofor example, a school sun safety education program combined witha mass media campaign in a community.the most comprehensive examples of this type are from australia.education and policy interventions have beendemonstrated to be effective in schools from early childhood upto eighth grade, as well as outdoor recreational andoccupational settings. the u.s. preventative servicestask force has recommended provider counseling aboutminimizing exposure to uv

patients aged 10 to 24.the task force currently found insufficient evidence torecommend provider screening for the general population, in otherwords, clinical examination of the skin in the absence ofsymptoms for patients at average risk.the task force is currently re-reviewing the evidence oncancer screening. time and cost are key barriersto assessing cancer outcomes but there are some new studiesregarding skin cancer screening which are going to be includedin the updated review.

based on the existing evidence,acting surgeon general boris lushniak issued a call to actionto prevent skin cancer last year july 29st, 2014.cdc worked closely with the office of the surgeon general todevelop the document. based on the current evidence,the surgeon general outlined five broad overarching goals toprevent cases of skin cancer. the first goal aims to increaseopportunities for sun protection while outdoors in settings likerecreational areas and schools. the second goal addressescommunications about skin cancer

prevention and the need toidentify and disseminate effective prevention messages.the third goal relates to policies across all levels fromfederal to state and local and it includes organizationalpolicies, as well as legislative.for example, school policies can help support skin cancerprevention in a number of ways. the fourth goal relates toreducing harms from indoor tanning and the fifth goalrelates to strengthening research and increasing ourunderstanding of how best to

prevent skin cancers in thefuture. thank you, and the next speakerwill be sharon mckenna from the arizona department of health.>> thank you, meg. it's exciting to be here todayto share with you my personal experience implementing sunsafety. i became a sun safety advocatein 2002 after my first melanoma diagnosis.clinical trial nurse urged me to contact the state health department. i told her after my diagnosis, iwas stunned to learn that

childhood exposure toultraviolet radiation has a huge impact on whether a person willdevelop skin cancer. i took her advice.i met with the health department and shortly after i was giventhe job opportunity of a lifetime to create and implementa sun safety program. it was a grassroots door-to-dooreffort starting with my then kindergartener school.i called and asked for ten minutes to speak about sunsafety during a staff meeting. i phoned school after schoolrequesting the same thing, and

those ten-minute talks led to anhour-long presentation, and today i can give about 300school presentations across our state.i get paid to obsess about my affliction.after 31 biopsies, lesions, and diagnoses of all three forms ofskin cancer, i am one among millions of skin cancer patientswho likely had no idea that skin cancer is the most common yetmost preventable of all cancers. arizona, where i'm from, if acountry would rank number two in the world in skin cancerincidence and we have over 300

sunny days.our warm climate allows us to wear t-shirts and shorts in thewinter resulting in year-round exposure than in colder climates. we were able to bring attentionto sun safety which enabled our agency to make it a toppriority. every time i go out, everyoutreach activity performed, every e-mail i send, everypotential partner i approach is asked to share a sup safetymessage, embrace it, and adopt it.as meg mentioned, state cancer

registries collect melanomadata. arizona's invasive melanoma rateis somewhat higher than the national rate but we in thefield thought our rates were a little bit lower than weexpected so a melanoma task force was formed to compare thenumber of cases received by our registry with the number ofcases logged with an individual dermatology practices bypreparing cases recorded to cases treated, we found anunreported rate of 70%. now we are collecting the datafrom the state's 531

dermatologists.we've revised the melanoma reporting form.we created a monthly newsletter focused on helping providersimprove reporting requirements, and once that data is cleaned,we can map and rank arizona in terms of highest to lowestmelanoma rates and while we can't yet pinpoint what causesone neighborhood in our state to have triple the melanoma ratesof another we can reach people in all 127 census blockneighborhoods simply by reporting our findings to themedia, so that everyone can

learn how to protect themselves.we are proud that arizona is the first state to pass a sun safetyeducation mandate. over 700,000 students in 1,100 kthrough eight schools learn how to protect their skin andprevent skin cancer. private and non-traditionalschools can also use the program voluntarily and we've formedpartnerships with over 250 organizations.success in this state recently led to programs expansion tochild care sites. under our empower program over2,400 child care providers are

required to meet our sun safetystandard with detailed protocols for applying sunscreen andproviding outdoor shaded play areas.this program reaches 20,000 children ages birth through 12and the great thing is, this is consistent with the communityguides, community preventative services guide and the surgeongeneral's call to action to prevent skin cancer.we are expanding through the sectors.so our initial goals were to protect kids and reduce uvexposure.

we adapted the free epa sun lifeprogram with easy-to-use curriculum activities that havebackgrounds in science, math and social studies, that average 20minutes and are categorized by grade level.we modified the curriculum to meet our state standards, wrotetip sheets and created a physical education module toshow kids how to be active outside and sun safe.we're turning sun safety messages into daily and lifelonghabits. sunburn and suntans can causeskin cancer so use a broad

spectrum sunscreen and lip balmwith an spf, sun protection factor of 15 or higher, protectyour eyes with sunglasses, wear a hat with a wide brim, seekshade, and under a tree, awnings or indoor especially during peakmidday sun. in arizona some offices havebuckets of umbrellas so you can use them walking outdoors orfrom building to building to a meeting.we ask new schools be built to optimized shadows and shade castespecially during midday lunch recess and some tvmeteorologists announce the uv

index which tells us how muchprotection is needed to prevent sunburn and suntan on any givenday, and of course, avoid sun lamps and tanning booths.artificial sources of uv are just as dangerous as the sun'snatural radiation. simply, keep your skin the colorit was born in. we're helping schools expandtheir commitment the to sup safety with strong policies.we provide a sun safety policy template to our 2,800 k through12 schools so they don't have to create something from scratch.our policy, not only allows but

encourage sun safety practicesbecause in some schools wearing hats and using sunscreen is notallowed. remember the easier you makeimplementation for the people you're asking to do it, thesooner it will occur. we reiterate the communityguide's recommendations primary safety school education is veryeffective in increasing sun protection among kids.in fact our arizona study of 281 k through eight school educatorsduring a seven-year period found a 63% increase in studentability to provide examples of

the harmful effects of the sunon skin, and that ability to provide examples is up 25% sincewe first asked the question in 2007.and 85% of our respondents cited arizona as their primary sourceof sun safety education. as mentioned we offer a policytemplate and this is just a brief excerpt, just the firstparagraph of a two-page fill in the blank policy that schoolscan use, adopt or expand on if they wish.and we always recommend in creating a sun safety policythat you use the trusted

educator and child care sourcesthat limit, that promote limiting sun safety policiesamong children. so phase two, proliferate.the more successful you become, the more partners you'llattract, the more people you can reach.in 2003, the phoenix zoo allowed us to provide animal themed tipsheets to patrons that evolved into sun safety murals onbathroom walls and thousands of students this summer are able toget sunscreen and wide brimmed hats as part of their sun safetyuniform.

skin cancer has become a topfive priority in programs i never dreamed possible, simplybecause i asked, came to the table, armed with somecompelling facts, and promised that we would support theirefforts. new empower schools program isbeing piloted for k through 12 schools who received usdanational lunch services and this might be an opportunity for yourstates to someday incorporate sun safety.supply people and partners with subject matter.we tweet, blog, provide updates

on trends and policies much fromthe brilliant collaborators we work with here at cdc and aroundthe world. we've learned a lot of lessons.i believe no only means not right now.keep plugging away. measure the processes andoutcomes of your skin cancers.i initially thought that contacting schoolsuperintendents would open the doors to sun safety education,but quickly found that approaching individual schoolsyielded much better results, and

one sun safety assembly couldlead to a statewide version of school district training.use the tools you already have at your disposal and identifythe data your state collected. for example cancer registrydata, behavioral risk factor survey surveillance data thatsometimes reveals adult sun behaviors.policies can be effective at even the smallest level.start with one intervention, one high risk group you have thegreatest chance of reaching and partner widely outside publichealth sectors to reach people

who don't yet know that sun andsun lamps can cause skin cancer. i remind students at the end ofevery assembly, you are my first generation of sun safe kids.now you know how to protect your skin and prevent skin cancer.tell everybody what you've learned and be a role model.tomorrow, i hope you'll e-mail the grand rounds links to yourfriends, family, school nurse, and anyone you think couldbenefit from it, with one short sentence that says "i think thisinformation would be wonderful to include in the upcomingnewsletter or blog."

i thank you for sharing the sunsafety message and letting me talk today. our next speaker isdr. jeff gershenwald. [ applause ] good afternoon.i'm jeff gershenwald. i'm a surgical oncologist andmedical director of the melanoma and skin cancer center at theuniversity of texas and cancer center in houston, texas.in addition to an active clinical practice focused onmelanoma i also lead and

participate in research onmelanoma. i'd like to introduce you to arelatively new team science research program at md andersoncalled the melanoma moonshoot. m.d. anderson cancer centersmoonshot program aims to accelerate the pace ofconverting scientific discoveries into clinicallyimpactful advances that reduce cancer deaths.i have the privilege of co-leading with mike davies, amelanoma medical oncologist and physician scientist.we work with a large research

team that represents manydisciplines. melanoma was chose as one ofm.d. anderson's moonshot programs because we have a verylarge clinical and research program and a clear vision withdetailed goals and implementation plans.programs and leadership were considered to have significantpotential to leverage advances and scientific knowledge towardsmaximal impact and making a difference for our patients andthose who are not yet patients. more specifically, we know thatwhen detected early, melanoma is

treatable and often curable butoutcomes can vary widely across patients.for patients with advanced disease there's been poorlong-term survival. nonetheless, recent advanceshave transformed our understanding of melanomamolecular biology and immunology and these scientific advanceshave opened the door to targeted and immunotherapies alike.there's clear and compelling epidemiologic evidence that uvradiation both from the sun and from indoor tanning devicescontributes to melanoma risk.

the role of uv is also supportedby recent research on genetic mutations in melanoma, researchadvances include work with the melanoma cancer genome atlasprogram which i've had the privilege of coleading over thelast five years. recent studies from the programoverall have shown that melanoma has the highest mutation rateany of cancer analyzed thus far to date.this cancer plot shows how often mutations occur.the plot shows about 40 tumor types arranged with increasingfrequency according to the

overall frequency of somatic ortumor-based mutations. melanoma is at the extremeright. in the plot, each dot representsthe frequency of mutations in an individual melanoma tumor.taken together we can see that melanoma has the highestfrequency of mutations across this enter panel.please note the large mostly yellow box below melanoma.it is color coded to display the type of mutation.in this graph yellow indicates most of the yellow are c to t,transition plan, classic by

associated with a uv signature.this provides further evidence for the role of uv radiation inmelanoma. the goals of the melanoma moonshot are to reduce the incidence and increase the proportion ofpatients diagnosed with early stage potentially curablemelanoma to personalized manage the strategies in clinicallylocalized melanoma and to improve long-term diseasecontrol and survival in advanced melanoma through personalizedtreatment approaches. there are two initial flagshipprojects.

the first involves primaryprevention of melanoma through uv radiation protection andyouth led by mary tripp, susan peterson and ellen gritz ofthe department of human sciences.the second integrated analyses and targeted of key cancer genesand better personalized care and increased long-term survival inmelanoma. i lead this latter project withmike davies. we'll focus on the melanomaprevention flagship, which focuses on working with youthand increasing their use of uv

protection, decreasing their sunexposure, and decreasing their tanning behavior.these objectives can achieve the long-term goal of reducing theincidence of melanoma and the project includes activities tosupport, facilitate and evaluate legislative activities andmaximize reach and impact of evidence-based interventions.the prevention flagship will initially focus on primaryprevention of melanoma across the age continuum.initial efforts are dissemination for pre-k withsimilar activities planned for

kindergarten through secondgrade. uv phototography protocol is being targeted to middle school students that we'll talk aboutin just a moment and soon embark on indoor tanning facilitylegislation, compliance and research efforts that as notedby meg targets behaviors common in high school.finally, i'll introduce a skin cancer prevention toolkitinitiative that's being developed for colleges anduniversities. the aim of the preschoolcurriculum is to teach children

about sun protection and promotesafe behaviors in an effort to reduce the child's chances ofdeveloping skin cancer later in life.sun protection is actually a superpower.the central idea is the superhero characters travelaround the world and each has a sun safe superpower to protecthim or herself against the harmful effects of the sun'srays. in the center here is ray, andhe's part of ray and the sunbeatables.ray is the leader, he's in the

center and has a superpower ofshade, and he also knows when it's safe to be outdoors.ray wears the magic watch that reminds him to be superprotected from 10:00 a.m. to 4:00 p.m. when the sun's raysare most harmful. left to right, chloe, serena,stefan and hannah have superpowers of protectiveclothing, sunscreen, protective sunglasses and protective hats.our strategy includes the recently announced collaborationwith the catch global foundation an acronym for coordinatedapproach to child health.

catch includes programs forearly childhood educational and afterschool components.the original catch study was the largest school-based healthpromotion study ever conducted in the united states.catch has a history of 25 years of research and real worldimplementation, and currently reaches approximately 50% oftexas school districts. we're also expanding ourcurriculum for k through second grade.consistent with the surgeon general's call to action goalsthe curriculum emphasizes

providing individuals with theinformation they need to make informed healthy choices aboutultraviolet radiation exposure. we have aligned these activitiesto the state's standards as well as the common core and nationalstandards. as a component of the melanomamoon shot m.d. anderson informs legislators in texas about thelink between indoor tanning and skin cancer.in 2013 texas legislators passed sb-329 which prohibits indoortanning bed use for persons under 18 years of age.texas was the fourth state in

the united states to enact sucha law. and this was really a tremendouseffort collaborative across the platform at md anderson,government relations team, multiple medical societies,foundations and several of our patients.by 2014, there were 11 states that had passed under 18 tanningbed prohibitions, and were actively involved now inproviding technical assistance and education across otherstates that are considering similar legislation.md anderson has continued to use

its experience to help insupport similar efforts in nine other states to date from coastto coast, including arizona, where sharon comes from.understanding how the legislation is implemented andhow well tanning facilities comply with the ban is acritical next step. we'll begin a new study todetermine the proportion of texas tanning facilities thatcomply with sb-329 soon. we'll be examining complianceamong 1,100 facilities licensed by the texas department of statehealth services.

there have been some recentchanges in the regulation of indoor tanning devices in theunited states that also provide some important opportunities forprevention. the fda recently changed theclassification of indoor tanning devices from class one devicesshown here prior to may of 2014 to a class two device as of mayof 2014. this is remarkable, becausepreviously as you can see here, tanning beds were in the samecategory as tongue depressors and elastic bandages likeband-aids.

changing the classification toclass two devices has meant that tanning beds are now includedwith x-ray machines and other specialty uv lamps fordermatologic disorders. the fda issued a black boxwarning required for use on tanning devices that states"this sun lamp product should not be used on persons under theage of 18 years." to leverage these preventionopportunities we're reaching out to the medical community onissues related to indoor tanning.one example of this is a

recently published editorial inthe march issue of "the annals of surgical oncology" highlightsthe important of educating policymakers of the harmfuleffects of uv exposure for youth and highlight the fda's recentblack box warning. can we improve sun protectionadolescents? recent search has examinedappearance focused interventions to reduce indoor tanning and sunexposure behaviors. uv photography is used as anappearance focus intervention to increase sun protection behaviorand decrease sun bathing and

indoor tanning in adults.moon shot will be done for adolescents in middle school andthe intervention involves taking a standard and uv photo of theface, using a rah with a uv filter that provides an imagerepresentation of skin damage due to uv radiation exposure.we'll study whether the intervention is effective inincreasing adolescent sun protection behaviors and acts todecrease tanning behaviors and sunburns.i also want to mention work related to college anduniversity campus.

the skin cancer prevention toolkit is in development and through a partnership with theamerican cancer society cancer action network, our goal is tomake advances in eliminating indoor tanning devices fromcolleges and university campuses.the tool kit will provide resources and tools for highereducation administrators to adopt skin cancer preventionpolicies and commit to eliminating student use ofindoor tanning devices. the toolkit will include acomprehensive collection of

facts, policy templates,education and resources to implement skin cancer preventionefforts on campus. i'd like to acknowledge themultidisciplinary team that is such an integral part of ourmelanoma moon shot. liz burton is our scientificproject director. mary, susan and ellen led andcurrently lead our prevention flagship, payal and mandy jo onthe right are the program managers and ernie hawk, markmoreno lead the moon shot prevention and control platform.finally as i thank you for your

attention i acknowledge thegenerous support of the multiple individuals who thus far madethe melanoma moon shot possible. i'd like to now introduce deputy surgeon general boris lushniak.>> thank you, jeff. i'm here to be the closer.it's kind of interesting how this is very much akin to whatgoes on with the issuing of call to action.meg was very kind in terms of saying, well, cdc approached theoffice of the surgeon general and we kind of helped out.let me tell you the truth.

right?the truth with surgeon general's reports and calls to action isall, if not most of the work is done by others.that's the truth. and in this case, we have anincredible partnership with cdc in issuing this call to action,but i give kudos to meg, to the whole team that worked on thiscall to action, because ultimately it's akin to what wehave in the football game. i'm not a big sports guy but inthe football game, right, when you start advancing the ballfrom your own 1 yard line, all

this work is done.and that's the way i view call to action.all this work is done in this case by cdc, by several of ourother partners i'll go through quickly, but at the end theybring it down to the 1 yard line and then the fancy guy in thefancy uniform gets to score the touchdown.right? that's the photo image, and atthe end of that, it's back to the concept of the surgeongeneral's office being the bully pulpit, right, that we come outthere in the uniform and say,

listen, america, this is whatneeds to be done with skin cancer prevention.photo-ops are taken, you get the interviews about but i'm thefirst to acknowledge that a lot of the work, the grunt work, thepushing of that ball ahead took place by many others.so what do we know? i'm the finisher here in thisesteemed panel as well, so i'm at the 1 yard line, taking theability to put all this together yet again, lucky guy in theuniform. but in fact, what we epitomizehere in front of you is in fact

how we advance the ball inpublic health. notice the partnerships here atthis very table. it started out with the feds,the cdc approach. we ended up at the state andactivist approach, and then the world of medical prevention andacademic approach to this, and then we bring in the bullypulpit, the ability for the surgeon general's office to berepresented and say here's where we should be heading.so it is a major public health problem.we talked already about the

increasing disease burden, thecosts, the rates of skin cancer being a problem, a public healthproblem in this united states, one that we can't ignore, andonce again, the ability for us to put all this together to saynow's the time to advance it. we're in the 21st century.we're discussing with jeff earlier today saying in the 21stcentury if there's anything that we've learned is the ability towe will do better in diagnostics.we will do better in therapeutics but ultimately theanswer to so many of our

national problems including skincancer is the prevention side of the house.that's where we have to get better and how are we going todo this? through these types of partner-ships, community partners, business, agencies, individualsuniting around a common cause. now this document which i'llrefer to several times, the call to action, why did it takeplace? you know, when i go back in timeand at that meeting dr. howard ko, the assistant secretary forpublic health by the way a

person who has dermatologicaltraining and interested in the subject matter, in the room isthe deputy surgeon general who happens to be a dermatologistand interested in this subject matter and an interested partyin cdc and we walked away from the meeting two plus years agonow saying we can do this. as happened that deputy becamethe acting and things moved much more quick will you but what itis, is a call to action. i love that term because it'snot a surgeon general's report. it's not just coming out theresaying here's the facts.

it's in essence saying we havemore work to do in this arena, a science-based document tostimulate that action nationwide to solve this problem, it raisesawareness because as brian williams, now a controversialfigure, on the "nightly news" that night of the releaselooking sternly into the camera, a tanned brian williams mindyou, and said these words "in the 143-year history of theoffice of the surgeon general, this has never happened."what happened was, an awareness. it's not like we changed theworld by putting out the

information the call to action.lot of this was already known. it's the fact that it ended upin the hands for that last yard for a message to come from amessenger that, for the longest time, was not talking about thisissue. yes there's a million issues inpublic health we could talk about but that was all abouttime and place. in the 14 -year history of theoffice of the surgeon general this has never happened, soprovide clear action steps to move forward on the subjectmatter.

now the partnerships that existout there again, government wide and beyond government.an important role here is the national council on skin cancerprevention that brings multiple organizations together, thatwaves the flag of skin cancer awareness and prevention, andpartnerships with groups like the american cancer society, theamerican academy of dermatology, and now after the report showedeven more so the important impetus that the work is notjust done by the feds here. long ago we've gone beyond thecensus, we're the feds, we can

do it all, no.nothing moves in public health until we establish thosepartnerships and many of our partners are shown here on thisslide. it begins at the local level.one of the first things i did after the issuing of this reportis we went down to do a meeting, down in new mexico, and outsideof albuquerque or in albuquerque bandeller elementaryschool was a sense of what could be done.this was much like your story, right?it was the sense that at an

activist level, it was parentsyears ago saying we have an issue in new mexico and our kidsare playing in these areas that don't have shade.and yes, there was resistance. yes, there was this, you know,inability to make things happen quickly, but ultimately ithappened. now you have this whole schoolthat's really dedicated to teaching kids about playing isimportant, being outside is important, but taking care andpreventing damage from ultraviolet radiation is just asimportant.

you know, there's almost a riteof passage in this student population as newkindergarteners would come in, the older kids, right, the bigkids on campus, the sixth graders would turn to theyounger kids and they would be the ones issuing the sunprotective hat. it was welcome to the school,this is what we do here, and i love this photograph, becausepartially you would say as a photographer, oh, there's toomuch shade in that photograph, but in fact it's shady for areason, folks.

and notice that the only personnot fully protected is the acting surgeon general at thetime, he has a short sleeved shirt on and not a veryprotective head cover. so what do we do?in terms of the strategies we heard from meg earlier todayabout the strategies, in terms of call to action, what do wedo? we talk about what we've donealready, incorporate sun safety education policies in school,support that shade planning in land use development.yes, this is where groups like

architects and planningassociation and parks and recreation people play a role inpartnerships and public health. yes, i grew up at niosh and inthat world of occupational safety and health there's a roleof protecting outdoor workers from that very same exposure andcertainly looking at the indoor tanning laws as described it's akey feature. we have an industry out thereselling a known carcinogen to a vulnerable population.what the hell are we doing about it?right?

what are we able to move aheadon in terms of protecting people, providing to them theright information. i'm not here to overregulateeverybody but at the end of the day, how many of those youngkids who are going to tanning booths realize that this is aknown carcinogen that will be problematic?and certainly providers, their role in terms of counselingpatients and hopefully making break-throughs with furtherinformation about screening, and its ability to play a role interms of prevention.

so millions of teens areexposing themselves to this unprotected ultravioletradiation and yes, there are changes in motion, world healthorganization 2009, this is a known carcinogen.we heard about the fda changes in terms of their regulatoryapproach as a class two device. we certainly have interest incongress, right, looking at groups that exist out therethat, in fact, are supporting an exposure to a known carcinogen.let's be honest here. you know, none of us volunteersto say hey, listen, i want to go

out this weekend and get asunburn. right?nobody says that. sunburn is bad, and yet how manycircumstances is it, you know, i was going through this earlierwith john on the vital signs videotape today, how many timeshave we returned from a vacation.you look great, you look tanned. in essence, tanning is a sign ofskin damage. and you look at the concept oftanning, whether natural light or artificial light, it is beingcondoned.

here is an example, at unc, 26%of chapel hill, north carolina, apartment complexes provideindoor tanning facilities to their renters.we've made headway in smoking, no smoking allowed in thebuilding, right, because that's a known carcinogen, secondhandsmoke but i have a tanning booth here, here!enjoy! to some extent we changed thesocial norms on smoking and the same thing needs to take placewith other known carcinogens. certainly positive is that ratesof indoor tanning have been

falling, 2009-2013 we've seensome declines. our hope is that we see effectfrom the increased awareness, certainly we look back at 2009and realize that when we look at indoor tanning restrictions forthose under 18, there was only some restrictions in a couple ofstates. we moved to 2012 by 2012,california became the first state to prohibit indoor tanningfor all minors younger than 18. vermont implemented an under 18ban in that same year, and then we move ahead now to 2014 and'15, note that blue is good

here.42 states implemented new laws or strengthened existing lawsabout indoor tanning amongst those minors.so in essence, we are pushing ahead and making this betterfrom a policy perspective, and how is that then translates toan effect on health? we know in states that havethose multiple youth restrictions with youth accessrestrictions the odds of indoor tanning among teen girls were42% less and our hope is that's going to be translated to adecrease of that burden of

disease.and still, we still have this concept of the social norms,even beyond the indoor tanning, more than one in three americansreport getting sunburn each year.who here got sunburned in the last year?raise your hand. guess what?the deputy surgeon general did, too, so i blew it, right?i blew it. but the reality is that's not agood thing. we have to have that sense ofawareness when we're outdoors,

and we condone from the oppositesurgeon general, go out, have a good time.it's about physical fitness, it's about getting outdoors,it's about bicycling and kayaking and swimming andrunning and walking, but protect yourself from that knowncarcinogen, and certainly when it comes to indoor tanning, onceagain, we have to look at it for a fact.it's an industry that is selling a known carcinogen.so overall we still have a lot to do in the realm of healthcommunication and health

education.so the next steps. we continue on this pathway,using the call to action. i ask you all, look it uponline. look through it.implement it into your own lives.certainly we at cdc have to be those examples for a healthylife, an active life, but a healthy life.comprehensive community-wide efforts to prevent skin cancercan work and with adequate support and a unified approach,we will be successful.

and we look at success storiesout there, right? we looked at the ability forarizona to turn the tide. we looked at the ability form.d. anderson to be able to implement laws within the stateof texas. we look internationally atcommunity programs within sunsmart in australia shows thatskin cancer prevention saves lives and saves money.every dollar invested in sunsmart australia saves morethan double in health care costs in that nation.so i finish where i started.

right?the guy in the uniform, passing this message through on thatlast 1 yard line. i thank you first and foremostfor your attention for being here.i thank you for organizing all this, cdc, but most importantly,the message really is, take care of ourselves.summertime, it's a beautiful spring day here, summertime isaround the corner, just be careful with your skin, and oneof the images i didn't portray here but spent two monthscommanding our monrovia medical

units in liberia and one of thephotographs i have is in the midst of the ebola crisis,right, our officers go into the hot zone fully covered,protecting themselves against this microbe, this deadlybiologic agent. and that's not how i want themto protect themselves against ultraviolet radiation but at thesame time, the other imagery i have is of those same officersin the very hot liberian sun, putting on their sunscreen.yes, rolling down their sleeves on their field uniforms.yes, wearing the goofy booming

hats which provide shade.that's the image that at the same time you protect yourselffrom ebola, you're also protecting yourself fromultraviolet radiation. it is doable by all of us.i thank you so much for your attention.[ applause ] i changed the slide.>> thank you, admiral lushniak. i want to open the floor forquestions. i think we've got about fiveminutes if you're in the room or online.please remember to keep your

questions brief so we have timeto answer as many questions as possible.>> we have a question from our online audience for admirallushniak. "you mentioned that tanned skinis a sign of damaged skin and yet artificial tanning hasbecome a part of societal norms. what can we do individually andas a society to change the norms and behaviors?">> you know, to a large extent we almost have to look back atthe tobacco situation. what helped us with tobacco withsocial norms was in fact what?

the messaging of secondhandsmoke when it became a bigger issue.when you light up, you bother me.i don't think we'll see that help coming out of the skincancer world. i think part of it is the ideaof, from a health communication aspect and health literacyaspect, we throw in the issue of disparities, how do we getmessaging out when things are not good for people, and i thinkit really, that's the approach we need to look at this, it's ahealth communication endeavor,

how do we sell this idea this isa known carcinogen, from several perspectives.we know certainly in the teen and young adult population theconcept of skin cancer is not necessary.we've tried this with tobacco. you'll die of cancer, don'tlight up. that message doesn't work bututilizing other effects which is, everyone's deathly afraid --so why do you tan? i have two daughters.couple weeks ago we're vacationing in key west, both ofthem are lying out "but dad, we

want to look pretty because theprom's coming up." right?even the acting or the deputy surgeon general has that issueand ultimately, i'm still battling that, but the sense is,guess what? you know, this prettiness"prettiness" in the short run, i'm not bringing out the cancerthing yet but i'm saying you want to have really ugly skin?it's going to happen quickly. you want to be wrinkled andappear older than you are? my younger child bought off onthis, she is proud her skin is

actually very pale and prettyand i'm working on my older one, so when you figure it out, letme know. do we have any otherquestions? yes, another question fromour online audience, "if you build a slow tan using thetanning bed so that you won't burn when outside, is that worsethan burning?" i'll tackle it initially andmaybe we can go to -- you know the reality is that this idea ofhaving a protective tan, so it was common for a while there,i'm not sure how common, i'm

heading off on this cruise, i'lldo a few sessions so that i don't burn.yes, there is a protective effect.the spf factor of a tan is on the order of two to six.so even though you think you're out there protecting yourself,the reality is you're just allowing yourself to actuallyhave excessive ultraviolet exposure even more.you still can break through with a burn based on exposure andgives you this false sense of awareness i'm fully protected.you're not protected.

you're protected when you're inthe shade enjoying that cruise, when you're putting onprotective clothing while enjoying that cruise, whenyou're putting on the spf factored sun broad-based, sunprotective products, right, so there is a way to have fun andyet not have to subject yourself to known carcinogen.>> next question, i see a question in the room.>> yes, hi, thank you. so it does seem like the beautyculture specifically with teenaged girls is going to beone of the hardest to combat.

i was guilty of being one ofthose teenaged girls going to prom.has there been any movement in promoting alternatives, so inpromoting spray tanning or any kind of products that sort offake the tan but are safer, and do we know whether or notthey're safer? so the fda regulates theingredients that are in spray tans but they're not used to be inhaled. if you've ever been in a spraytanning both, i haven't, but i understand it's very difficultto avoid inhaling those so we

cannot recommend that as analternative. i should also say that althoughwe don't specifically recommend it, there are products on themarket which can be applied directly to the skin, you know,diy, over-the-counter, which may be an alternative for somepeople. and i think there's also alittle bit of debate over do we recommend alternatives or do wework on sort of changing social norms so we're comfortable inthe skip that we're in. another one from our socialmedia audience.

it was mentioned that screeningis not recommended for the general public.should it be recommended for individuals with a large numberof risk factors such as pale skin, family history, and thehistory of many sunburns? that's a great question toask your family doctor. i'm going to step into thisone, all right? so far, u.s. preventativeservices task force is looking at data, right?as a dermatologist, right, or as a surgical oncologist, we lookat data and say okay, it hasn't

been proven to be cost-effectiveto have everybody screened, and yet, you know, wearing my otherhat i'm a member of the american academy of dermatology thatevery year conducts cancer screening as part of theircommunity engagement. i, for the longest time when iwas at niosh in cincinnati did annual screening within ourfacility there, and so the idea is that, you know, we realizethat we're waiting on data. the u.s. preventative servicestask force is looking at the recent data from germany on thisand our hope is there will be

some modifications on thescreening concept. until now, because we do believein the u.s. preventative services task force and its highcriteria of proving what works and what doesn't, what it saysabout general screen something inconclusive.what it says about counseling is conclusive for specific agegroups and specific fair-skinned populations.in the clinical world, what you'll see is someone who hashad a preskin cancer, for example keratosis, usually thereare multiple, someone who had a

basal cell, squamous cell ormelanoma is often time counseled by their physicians to followup. there's two roles of sort ofroutes of following up. one is the cell screening, whichis all of you here should be doing that, there is no economiccost associated with that, there is no sense of, you know,reimbursement, no sense of insurance cost, which is get toknow your bodies. get to know your skin.if you have somebody who is not, where it's not problematic forthem to check you out, if you

know what i mean, have them helpyou look at the areas you can't see.if not, strategic use of mirrors is great, and all you're doingin this case is, if there's anything that looks kind ofweird to you, note it. and there's two routes.take it to your physician, to your health care provider andsay hey, listen, i noticed this spot, or if it's been there fora while, take a photograph of it.everybody's doing selfies. do selfies of your lesions,right, and monitor it yourself,

right, which is you're lookingfor changes, changes in size, shape, color, or symptomsassociated with it, signs associated with it.so we have a burden here as well, but certainly anybody whohas had a history oftentimes will be consulted, follow upwith me, six months, a year from now, and in the meantime monitoranything. i'd like to thank ourspeakers/heroes one more time. [ applause ]and all of the material associated with this sessionwill be posted on the web within

the next 72 hours or so, andplease join us next month for the next session of cdc publichealth grand rounds.

Cancer Research Uk Prostate Cancer

daniel katsner:all right. hi, i’m dan katsner. i’m the scientific director of the national humangenome research institute, and it’s my enormous pleasure to welcome you this afternoon tothe jeffrey m. trent lecture. jeff trent, as many of you know, was the first scientificdirector of the nhgri, and he was, of course, the founding scientific director, startingin 1993, and really, jeff, over the course of a nine-year span, built the intramuralresearch program of the nhgri into, i think, a real powerhouse of human genetics and genomics.jeff, of course, went on, after his very successful scientific directorship, to be the founderof tgen, the translational genomics research foundation in phoenix, arizona. jeff couldn’tbe with us here today, but is still very actively

involved in his chosen field of cancer genetics,and in 2003, the jeffrey m. trent lecture in cancer research was initiated by the intramuralprogram of the nhgri in order to invite leading figures in the world of cancer genetics whowould embody some of the same ideals of energy, and enthusiasm, and imagination, and reallyraw intelligence to the world of cancer genetics. and so, it’s my enormous pleasure to introducethis year’s jeffrey m. trent lecturer, and that is dr. stephen chanock, who is the directorof the division of cancer epidemiology and genetics of the national cancer institute,and steve is truly someone who falls into that mold of the jeffrey m. trent lectureship.steve is someone who has been, for a number of years, the leading figure in the studyof susceptibility loci for human cancers,

who has been a leader of the efforts of thecancer institute, and is also, i would say, a renaissance man, and a real mensch, as well.so, dr. chanock got his undergraduate degree, actually, at princeton university in 1978,and his a.b. was actually in music, and i understand that he may be breaking into songat some point -- [laughter] -- in the course of his presentation. in anycase, he went on to harvard medical school, and got his doctorate in medicine in 1983,and then went on to do his further clinical training in boston, in pediatrics, and inpediatric infectious diseases, and in pediatric hematology oncology, and he did research atboston children’s hospital, and the dana-farber

institute, with the legendary and still-activestuart orkin, studying molecular biology and human genetics, really, at its inception ofthe modern era. so, dr. chanock then came to the nih in 1991 as a medical staff fellow,or senior staff fellow, i guess it was, in the pediatric oncology branch. he went onto become tenure-tracked, and in 2001, received tenure. and over the course of the subsequentyears, he’s advanced, in terms of his career, in the national cancer institute, and in 2013-- august of 2013, he was named to his current position as the director the dceg. really, he has, as i’ve mentioned, doneenormously in terms of his science, and in terms of his administrative things, but ithink that something that really stands out,

in my mind, is something that’s a real measureof the man, and that is that since 1995, he has been the medical director of camp fantastic,which is a camp for children with various pediatric cancers that’s held every summerfor a week, and it’s run by the national cancer institute, and special love, incorporated.and so, anyways, i think that that’s just a telling sign of just the complete man, dr.steve chanock. so, steve, take it away. [applause] steve chanock:thank you very much for that lovely introduction. i want to assure you, i will not break intosong, i will not play the guitar, and i will leave it at that.

it is really an honor to be recipient of thislectureship named in honor of jeff trent, someone i know very well, who is a very dynamicand lively character, who i worked with on and off over the years. and energy and passionare two words that certainly come to mind when thinking about jeff, and his vision forwhere and how cancer research should go forward have been infused with those two, i think,very important qualities, along with his scientific rigor, and i think, you know, i’m sorrythat he’s not here, but, you know, i’ve corresponded with him quite a bit by emailin the last few days, and he was very happy to know that someone who was interested ingerm line, and primarily the germ line, would be speaking, because that’s a part of jeff’sportfolio. and today i will speak almost exclusively

about the germ line, but i think, in the contextof understanding how the germ line informs our understanding of the different types ofcancer that we encounter. so, let me start with question of heritabilityin cancer. we know that, going back to 1866, that paul broca, the famous neurobiologist,had observed heritability based in his own family, with breast cancer, with a numberof women in his family: sisters, aunts, mothers, and the like, and had actually published anddescribed this familial cluster, and then, in the interim, there were, you know, legionsof studies of twins’ families and siblings studies began to really assess what wouldreally be the risk if you had one particular cancer in a family, that another family memberwould have that, and that’s still an important

bolt-work, i think, how and in what way weprosecute the question of the genetic basis of cancer. in 1969, joe fraumeni with fredli observed the familiar clustering of multiple cancers in families, not just one cancer,but a number of them, and it subsequently identified that the mutations and the tp53gene are responsible for a high fraction of the li-fraumeni patients, and they were ascertainedthrough these familial studies, and i’m going to come back to this question of lookingat li-fraumeni-like mutations in the population, particularly in osteosarcoma. and then, alknudson postulated two hypotheses for retinoblastoma, really a central tenet i think of how andin what way we look at germ line genetics, thinking of the diploid as the model, but,as i’ll talk a little bit later, the genome

does come apart, and we certainly know thatthere are many different ways in copy number states can vary. and then, finally, the chaseusing the technologies of the 90s -- the 80s and 90s, led to the first positional cloningof the familial breast cancer gene in ‘91, and then subsequently, by ‘94, it was describedas brca1. this is in the background of looking at heritability from an epidemiologic pointof view, where twin registries were really quite valuable -- or have been quite valuable,so this is an important table that i will come back to when i show you the current statusof how we are looking at the genome-wide association studies, to be able to explain a fractionof what we think would be the heritability. but, the key issue here is looking at theheritable factors for prostate, colon, bladder,

breast, and lung: five of the major cancersthat we face, and this issue of shared versus non-shared is an important question, whichreally underlines, we think, the importance of the germ line genetic susceptibility in-- you know, in the context of the different kinds of exposures, and i’ll come back tothat. so, at this point, i would say, why do westudy germ line susceptibility? well, we can try and explain the heritability of cancer.we certainly know about it clustering in families and distinct populations, but now, with thegenome project behind us, and the annotation of hapmap, and knowing what genetic variationlooks like in the common, we now have the tools to begin to really ask the questionin sporadic cancers, which represent probably

90, 92, 93 percent, depending on your definition.how can we explain genetic predisposition? we know that within families there are increasedrisks of breast and colon -- you know, for one and a half to twofold increase, just inthe general population. but i think the ability to look at genetic susceptibility is reallycrucial to begin to try and pull apart the many, many things that are contributing togenetic susceptibility. and then, of course, the value of this in using it for risk assessmentfor individuals, which, i would say, we are very far away from being able to do otherthan the familial, and i think we have to be very careful not to oversell precisionprevention, precision medicine, at this time, with respect to predicting individuals’specific risk for cancer. that’s a place

where we all want to go, but we have a lotof distance to traverse. but i think the population-based screening issue becomes very important, andhow we use the information that we have now, and that we’re about to have in front ofus, to begin to think about stratification, that may have no public health implications,for using screening trials, screening tools, and the like, and i think genetic variationis helpful for that. we get tremendous insights into the etiologyof cancer, the opportunity to look at gene and environment interactions, and, particularly,as i mentioned at the beginning, how the germ line informs somatic alterations. and then,of course, everyone is excited about pharmacogenomics, but this is a very difficult thing to pursue,and it’s, you know, we’re sort of at odds

with most of the industry because it’s notin their best interest for us to identify the 30 percent of the women who should getherceptin and exclude the 70 percent from being prescribed that drug. so, this is somethingthat sort of at a cultural level, as well as a scientific level, is really lagging behind.there are some very exciting examples but i am not going to really focus my talk onthat today. i do want to start my talk, and really separatethe spaces. when we think about cancer genetics, we really have at least four different spaces,as demarcated here. one is the germ line, which is where i’m going to spend most ofmy time talking, but we also have the somatic. those are the alterations, the actual tumorswe see in the ncis-like sequencing from tcga,

where we see all of the large-scale eventsthat have taken place. we know that we’re heavily in the range of discovery, but withvery little clinical action at this time, and i think we have to be very careful innot overselling what we can do with, particularly, the germ line information other than in veryselect circumstances. i think we all want to get to the next stage but we still havequite a ways to go. so, when we think about the germ line -- this is sort of the outlineof what i’m going to talk about today -- we know of at least 110 to maybe 115 cancer syndromes,where we know that there is a very important mutation in the germ line, that explains thefamilial clustering of cancers in a family or sets of families, and these are very importantin giving us very good insights into the cancer

biology cancer drivers, and i’ll come backto that. through the genome-wide association studies, which i’ll talk about, we knowthat there are some 470 regions, and there are literally thousands more to be discoveredas we supersize, and i try to make the argument for why we should continue doing that. weknow that the somatic -- when you look at the tcga and the icgc, the cancer genome atlas,the nhgri and nci joint effort has been a resounding success in beginning to get a portraitof the landscape of genetic alterations, and we see that there are these drivers, thosethings that we think are very important, and we use both frequency and biologic investigationin the laboratory, but we also recognize that there is heterogeneity and [unintelligible],that are real challenges.

now, if we go to the clinically actionable,of all the things that we see on the upper-left-hand corner, only in a small faction can we reallygo into the clinic and advise or talk to someone in what, we think, is a really, you know,sustainable and supportable position. in the same way, only a small number of agents havereally come to market -- it’s larger than this, this is an example of the targeted therapy,in where, i think, the precision medicine initiative that dr. varmus has certainly beentalking about, as a very important way in being able to target the alterations in thetumors that we would be able to actually intercede, and either stop or slow down the growth ofthose particular cancers. and we do this in the context of looking at tcga, where we’vehad extraordinary lessons that have come from

looking up and lining up all of the differentmutations, and seeing the spectrum. we can see, literally, a four-order-of-magnitudedifference in the number of mutations, and then the types of mutations. how many arereal drivers versus how many are passengers, and this is something that’s an importantelement that’s come out of the somatic sequencing, that i’ll come back to in the germ linein a minute. so, for instance, if we look at lung adeno c-a, lung adenocarcinoma, oneof the most common cancers, heavily driven by smoking, the attributable risk is somewhere,depending on who you’re talking to, 75 to 85 percent for this particular cancer, andwe can explain a fair number of the cases that we see having these mutations in genesthat are quite disruptive, that we understand

something about the biology, or see the frequencythereof, tells us that this is an important event. we have a number of agents that arevery important that could be used and are going into clinical trials right now thatare very exciting for lung adeno c-a, but this is probably further ahead than just aboutany of the other cancers. when we then look hard, and ask the questionnext, of how, and in what way, does this really like up with what we understand of the geneticarchitecture -- i want to take a step back, and we’re going to first talk about thisspace here, the rare alleles that are causing mendelian disease, or familial clusteringsof cancers, the brcas, the tp53s, the patch, and the like. and currently, at this time,we know of about 115, and they’re scattered

all across the genome, and the interestingthing is that they are almost all ascertained in families. they’re rare mutations, withvery strong effects. from an evolutionary point of view, it’s very hard to sustainthem in a population. there’s a lot of very interesting population genetics, and there’sa whole other lecture on the brca founder mutations that we certainly see, and then,we certainly can see ankh genes and tumor-suppressor genes. so, those are important with respectto the kind of, sort of, classical genetic models of whether you’re looking at autosomal-dominant,or autosomal-recessive, but we certainly can see these in these 115 genes or so that havebeen identified. if we look here at a classic brca1 pedigree, we know that, in most cases,having a brc mutation is not necessarily a

100 percent likelihood that that woman isgoing to develop breast cancer or varying cancers. depending on the specific mutation-- this is a very important point about where in the gene the mutation takes place, andthen, there are 24,990 other genes, not to mention the environmental exposures. so, youknow, there are large consortiums that are identifying what are the important clinicalmodifiers as well as biologic modifiers of brca1 and 2, and i think that this is a veryexciting thing that’s going forward, and we’re just beginning to identify maybe thefirst 10 or 12 regions of the genome that are interacting with brca1 that may be veryimportant in identifying -- in contributing to the risk of breast cancer. but, the questionis in what type of breast cancer, because

we know that there’s heterogeneity, thereare different types of breast cancers that do track with the brca1 and 2, but not perfectly.again, this notion of genetic determinism we have to get past, it’s a more complexscenario, and i think the further we get into this, the more we recognize these factorsthat we really need to be able to identify, and put together these critical, sort of,compendiums, or catalogs, to be able to then look in larger studies. so, if we look at these -- excuse me, 110genes, pardon me, interestingly enough, about a year ago, naz rahman in the uk, publisheda very nice paper in “nature,” in which she looked at, at that time, this questionof what fraction of those genes were identified

in the germ line as explaining a familialcancer that had already been identified in a somatic setting, not necessarily in thegene, or not necessarily in the cancer that was being identified in that family, but nonethelesswas considered to be an important driver. and interestingly enough, about 50 percent,at that time -- and now, if you revisited this, it’s probably up to about 65 percentof the familial cancers of these 115 -- have, you know -- the mutations are lying in a placethat we know somatically is very important in one or more cancers. so, these have highfrequencies, and the somatic mutations, again, are the important drivers, but i want to keepseparate the idea that what’s driving the cancer, once it starts, as opposed to wherethe germ line is, you know, a susceptibility

factor, and this is where we have to invokeknudson’s two-hit hypothesis in the retinoblastoma model, that you can start with a germ line,and then add a somatic event that happens on top of that, in certain key genes, andthen there’s a very high risk of cancer. so, when we looked at, you know, this particularlist, we certainly, in dcg, have had a long-standing interest in tp53 and the li-fraumeni syndrome,and the characterization thereof, and we had done a large, genome-wide association studyof osteosarcomas and found a few regions that looked to be very important to risk for osteosarcoma,but one of our junior faculty, lisa mirabello had a terrific idea to take those key samplesand sequence p53 with next-generation sequencing, not illumina, but ion torrent. there are othertechnologies that do work, you can be published,

for the young that are out there. it’s importantto recognize that, hard as it is to past that, but the issue was to look at our distributionof osteosarcoma. i show this because the punchline is going to basically show that there is adivide in terms of where we think the genetic susceptibility with respect to p53 is factoring.so, we also know that there are some other things, such as the recql4, the rothmund-thomsonsyndrome, hereditary retinoblastoma. we know that osteosarcoma can arise in other settings.so, it’s very interesting that we went and sequenced all of the p53 exons, the utr intronicflanking regions, and then we classified, on the basis of already the internationalclassification of the li-fraumeni syndrome mutations that are already in the ir database,and, then ones that are likely to be those

on the basis of predictive deleterious mutations,and then rare exonic variants, which had very low mass in the public database. so, when we looked at this data, what wasinteresting to see was roughly 10 percent of the children and young adults that hadosteosarcoma, none of whom had been ascertained through family studies and we had no evidenceof family history in these 765, were harboring one or more -- not more, but one of thesep53 mutations. and so, when we looked in a different way here, as you can see, the p53mutations by age overall, as opposed to looking at zero to 10, 10 to 19, 20 to 30, we couldsee that there was a break by the time of age 30. so, in other words, when we look atp53 and those mutations and osteosarcoma,

if they’re going to happen, they’re goingto happen earlier in life. and this is an important issue that’s very difficult withthe studies that have in hand now to really start to layer on age in terms of, when isthe risk really an important risk and when does it goes away and you can say that someoneis, pretty much, out of the woods. so, we thought that out findings were very important-- and they are getting published in jnci in the next week or two, and kudos to lisafor really pushing through on this -- that the young onset of osteosarcoma has a distinctgerm line genetic etiology compared to the adults, which we know. and then here’s thequestion, considering genetic counseling in p53 mutation testing, should this be introducedinto the children’s oncology groups? so,

there’s an active discussion now and we’veshown this data in europe, and the europeans are looking at this as well, asking the questionin the pediatric oncology clinic where you’re seeing, you know, children with osteosarcomaand young adults, should you be considering, you know, a more formal type of genetic counseling?we’re moving that way but, you know, this is discovery. this is very new. one is notsaying that this means that every osteosarcoma patient tomorrow should get screened for p53.i mean, we have to think hard about how we are going to study and validate this, butwe find that these are the kinds of exciting things that we’re getting in this discoveryseries and how and what way we move to the next level is clearly very important, becausethe other question is what other germ line

mutations lurk in the, you know, in the young-onsetosteosarcomas, and we have to ask the question, should we be sequencing more than p53, andthe answer is, of course, yes. so we are moving down that road towards exome sequencing nowand, potentially, whole genome sequencing. so i think, you know, it’s important torecognize that there is a whole spectrum of how we’re doing these analyses. so, if wecome back to this figure here and we see that there are these very rare, highly-penetrant,strong mutations that we see and then, as we bleed down into these lower frequency withsome moderate effects, these are the hard ones to be able to identify, and then, ofrecent, the genome-wide association era has really focused on common variants that havebeen implicated in gwas. and so, i do want

to talk about these because these are veryimportant in building a polygenic model, in seeing that there are many, many small effectsthat are contributing to the risk of both common and uncommon cancers. so, as we goforward, and we see, really, what is a genome-wide association study for those who have not conductedthose -- this is not for the weak of stomach. it’s not dissimilar to a vaccine study,where you start, you go a long period of time, and then there is a p value or set of p valuesthat you are either really happy with, or you’re really depressed. so it’s not for the weak of heart goingforward and doing these large-scale studies. but i think that the key issue here is startingwith case control studies, and whether you’re

in cohorts, as we’ve learned very good casecontrols and sometimes not-so-good case controls, we can use the large agglomeration of casesto be able, with adequate controls, to be able to identify the big, top signals, butwe don’t really have the full panoply of all of the polygenic signals that are partof that. but as we go forward, we know that we go from the cases and their dna, to scanningthem, to doing the qc steps and the agnostic analysis, and this is really what’s differentabout genome-wide association studies. you look and the data tells you where there’san interesting area, you don’t say “gee, i always though the p53 was interesting inosteosarcoma, so i’m going to therefore look at that.”

that’s a very dangerous thing to do. andthen we have our manhattan plots in our replication, and these are stages that take a number ofyears but they are now part of the fabric of genetic susceptibility studies. and asyou can see here, as of december, the field now has about 475 that have been publishedin some 29 cancers, only one of them with a copy number variation, and interestinglyenough only about 8% are shared which raises this question of how much is the bias of howthese studies have been conducted versus what is the shared heritability. and i’ll comeback to this concept of shared heritability as we look at the large set of gwas that wehave, and try and compare them in some very sophisticated analyses.

and the other thing, what’s very interestingis, of these 475 or so, not -- almost none are associated with outcomes. so, it’s tellingus, i think, an important question that there are certain genetic regions that are veryimportant for risk for developing the cancer, but whether you go on and develop an aggressiveform of prostate cancer, or whether you survive breast cancer, ovarian cancer -- they arenot the same regions. it tells us the complexity of these things going on over an extendedperiod of time is really driven by a number of factors and, again, we are just beginningto pull apart what they are. so, if we take prostate cancer, as we can look here and seethere’s some hundred different regions -- it’s just like shotgun across the genome. they’rescattered but very few differentiated between

aggressive and non-aggressive. a number havebeen published, most of them died on the altar of attempted replication, and maybe two arethree that are able to actually survive, i think, stringent statistical significancewhich is very important, because whatever our findings are, there are wonderful post-docsand pre-docs who work on each of those regions, and you don’t want to send people off towork on false positives, and so, there is value in the genome-wide significance. so, for prostate, we really don’t see awhole lot of measure of things really coming together, whereas in testicular cancer, whichhas the highest familial risk -- what’s really interesting here is just about allthe hits, and they come at a much faster rate

relative to the number of cases scanned, where21 with another, i think, 11 getting ready to be published from conglomerating the studies,and you can see all of them -- localized genes that are important in telomeres regulation,germ cell development, sex differentiation, which has really been quite striking. it’sthe one cancer with the highest heritability as we know from the twin studies. monozygotictwins from the same are 75 fold increase. dizygnotics are 25 to 30. brothers are eightfold,so there’s clearly a very strong -- it’s a very rare cancer, so it does raise thisquestion of the issues of absolute risk, and we’ll come back to that. and i think, youknow, it’s also the one genome-wide association hit that’s of a high enough effect sizefrom the kit-ligand, which is an interesting

gene under selection having to do with haircolor, at this moment, but there have been some very eloquent papers in “cell” onthis, that it’s strong enough for a genetic counselor to actually think about wantingto give someone advice on the basis of being a homozygote. now, again, thinking about it,i don’t think at this point it’s ready to go into the clinic and, you know, mostgenetic counselors would not jump on this and say that this is something that we’regoing to do today, but again, this is where the discovery engine is now pushing and thestructure is how and in what way are we going to be able to address those questions. when we look a bit further -- so, for instance,one region becomes six. here, around the telomeres

gene, there are now ten different cancers,and the interesting thing with [unintelligible] and xiaoming [spelled phonetically] had reallyidentified, is that in each one of these regions, we saw kind of pleiotropy, where all six ofthe independent regions had some that are protective and some that are susceptible.so, in other words, the exact same allele in one disease can be a protection and theother can be susceptible, which really underscores the importance of looking at other genes and,more importantly i think, the environment. and the place where this is most confusing,is if you look at skin cancer. basal cell and melanoma are in the opposite of directions,pancreatic and lung, as well. so, you know, this is a very interesting region that weknow that there are highly-penetrant mutations

that are very important, as well, there. so, when assess these gwas regions, you know,there is this tension between wanting to look at all of them for risk purposes versus wantingto look at individual ones and go and do the fine mapping, and we do both, and where weknow one region becomes five, often they’re hidden in there and this is helping to explaina little bit more the heritability. some regions harbor alleles for many different cancers,and then we have to start asking the question, what about accounting for exposures like smokingand lung cancer, smoking and bladder cancer, and i’ll come back to bladder cancer ina minute, and then the question of the value of these large sets of snps, as we put togetherthese catalogs, the idea is, at what point

will they be of sufficient use to be ableto think about in terms of public health. at this point, it’s really very clear thatthey’re not ready for individuals, even though 23andme decode made -- a number ofgroups have tried to sell these over a period of time. it’s, you know, genetic snake oil.enough said on that. so, when we look at the gwas cancer susceptibilityhits themselves, when we look at these 475, we see a very different kind of biology underlyingthese particular regions. so, there are 470 unique regions, only about 25 percent of whichhave been explained. twenty percent are in regions where there’s no gene that is inany way connected to any of the correlated variance. so in other words, it’s doingsomething for some funny rna, or something

that’s important in genomic regulation.when we looked at this, less than five percent of the genes that fall under the peaks ofthese genome-wide association studies mapped to the cosmic database, unlike what i showedyou with the highly-penetrant mutations, where 50 percent was reported, and it looks likeit’s moving closer to 65 percent. nearly all of the gwas hits that we’re lookingat are looking at things that are really perturbations, that are changing pathways, but that are notnecessarily altering a particular gene. there are very few that are coding when we reallyexplain them. so, mitch makela [spelled phonetically] in the lab spent quite a bit of time lookingat the first blush of about 265 going, and really very carefully, looking at all thegenes and looking at cosmic, and we could

see that there was really no difference inthe kinds of mutations, the number and the types of mutations, between those genes thatwere under the peaks of gwas and those that would be randomly permuted based on genomiclocation, gc content, the kinds of things that we think of in terms of the locale thatmay be important in contributing to the risk for random or real mutations. so, now, we come back to this architectureof genetic susceptibility of cancer and we can see that we really have perturbationsof key pathways and the common variants, and each one is making a small dent that’s neithersufficient nor required for developing the cancer, unlike what we see in the familialsettings, where we really do have those damaging

drivers. so, as we look at this map, and seethat, well, with linkage studies and family studies, and, you know, historically we’refilling in this part of the space of any given cancer, and with gwas we’re going here,but in between these low-frequency variants that are part of this allogeneic model arevery tough to get at. and this is where next-generation sequencing and laboratory investigation reallyhave to hit the road. so, what i would now subscribe is that eachmajor cancer has a unique underlying genetic architecture and we are at different pointsin being able to build up the catalog of understanding what contributes to breast versus what contributesto prostate. there may be a few shared things, but nonetheless, they really are in our mindsvery important to build these models, because,

as we build these catalogs there may be increasingclinical utility as well as the obvious value of being able to use these catalogs, particularlyin common cancers, where, if you were able to stratify and ask the question of the changesin absolute risk for a common cancer, that may have real public health implications.for a very rare cancer, a shift in the absolute risk is a harder sell at this point. and so,i think, if we had, you know -- with infinite money, i would submit, if we are going toreally make an effort to have a complete catalog of what we think genetic variation looks like,one could make the argument that some of the common cancers are the places where we shouldput our money and, in fact, we’re doing that with the game-on and the oncorays, andthe like. we’re doing that with breast,

and prostate, and lung, and colon, and ovarian. so if we look at the genetic predispositionto breast cancer, you know, in 1994 i mentioned about the cloning of brca1, and shortly thereafter2, we can now look and see this kind of sweep, of having a number of genes that are highlypenetrant, but they are very rare, and then the gwas era has put a number there, but wehave very little in this space here, that we are now going after with xm sequencing,where we have to try and put together very, very clever stories. similarly, we can seethe doubling of the number of hits tells us that we can explain about 35 to 40 percentof the familial risk. and familial risk is defined here, we think, in these common cancers,as between 1 and a half to twofold increase.

so, if there’s someone with a prostate cancerdiagnosis or a breast cancer diagnosis in the family, there’s an increased risk thatsomeone else in that family has that. and this is a statistic to try and explain howand in what way can the snps -- the space of common variance, explain a fraction ofthat familial risk, because therein lies an opportunity to be able to then have stratificationbased on what we would see as a useful shift in the -- in that. so, prostate is lookingvery different. here, as you can see, there is virtually nothing in the high-risk, and,you know, for the snps it has been very, very exciting. so, for quite some time, nilanjanchatterjee, a colleague in dcg, and others have been looking at this question of, whatare the limits of using snps? because, at

one point, there was a lot of excitement,people were jumping all over, and suggesting like in crohn’s disease, where we have veryhigh sibling relative risk, that you could use snps to be able to move the auc in thearea under the curve, to be able to get close enough to a place where we would think itcould be clinically implemented. now, if we look at the common cancers, ofbreast, prostate, and colon -- when we were looking nilanjan and park have made some very,very important estimates based on empiric information, as well as, now being borne outby the larger consortium, that there are clearly limits to looking at the sibling risk modelof about two, for breast and prostate. and, in fact, he just yesterday was very kind tobe able to provide a very important new slide,

here, looking at it, we know that we can explain35 to 40 percent of the familial risk of breast cancer, which again, the issue is in the absoluterisk for screening, and the question of how we do that is still very much on the table.but, as you can see these curves, as we go from what’s empirically to what would potentiallybe known from going ahead and looking at as many as 500,000 cases and 500,000 controls,which is something that the world is moving towards. right now, there’s a big studyof roughly 150,000 breast cancers and 150,000 controls and that will continue on, and thatallows us to really identify what we think are, at least, on the order of estimated tobe 3,000 or more different snps. now, each of these may have their own story but it’sgoing to be decades before we understand what

those stories are, but the question is usingthis information in terms of risk assessment is a different question, and i think thatwe will be most effective in having as comprehensive a setup as possible. because, even if we justlook at prostate cancer risks -- as here from antones [spelled phonetically] [cough] inthe uk -- excuse me -- if you look at the 76 snps that have been identified, if youstart looking at the risk factors, and -- i mean, you look at the risk for developingthe disease, age is very important. and again, as we do these studies, we’ve been reallytwo-dimensional in our genome-wide association studies and many of our familial studies,and not really being able to assess the value of age and, particularly, of secondary factors,whether they’re environmental and/or, particularly,

other genetic affects. excuse me, for justa second. so, with that, i think, as an important storyto just delve into for a minute, with respect to looking at smoking. so, out of the genome-wideassociation studies of bladder, interestingly enough, a gene that had been identified bythe canada g [spelled phonetically] world of one of the four or five that had survivedthe 10,000 attempted publications that hadn’t really survived replication, using that toslow acetylation g, and, interestingly enough, you only see the effect in individuals whoare smokers. so, this really let us -- particularly with nilanjan, and nat, and montse garcia-closas,to look very closely at this question of the cumulative 30-year absolute risk, and someof the cohorts that are available to us, to

ask the question, what would be the risk fora 50-year-old male in the u.s., by looking at smoking in 12 snps, including the nat andthe nat2? as you can see, the r.d. here does separate quite nicely between the low-riskand the high-risk. this is not to say that we should start screening every potentialsmoker for bladder cancer. there are many other comorbid conditions and the like, butlet’s just do a thought experiment. that if we had 100,000 smokers with high geneticrisk who stopped smoking. we had effective cessation. if we are thinking about bladdercancer, where we have enough known about the genetic susceptibility, we would eliminate5,400 cases. this is just focused on only bladder cancer. if we then look at 100,000smokers with low genetic risk, and they stopped,

we would eliminate 1,500 cases. so it raisesthis question, of how and where we would apply these kinds of risk reduction strategies.so it’s a possible example, really, of how genetic and environmental stratification maytranslate into targeted prevention, the so-called “precision prevention,” but we are a longway from doing that, i think. the next sets of studies need to really assess and confirmthis and the question is, what are all the co-factors and the comorbidities of lung cancer,cardiovascular disease, and the like. so it’s really an important question but i think,you know, it’s that sort of exciting opportunity that really tells that we need to look very,very closely, and why we need to have, i think, these very large compendiums. [coughs] excuseme one second.

so, really, what fraction of the polygeniccomponent contributes to each cancer? so we’ve done scanning of over 100,000 individualsand 15 different cancers, and so josh sampson and our program, one of the young, terrificbiostatisticians, looked at 13 cancers, used the genotype snps to explain anywhere from10 to 50 percent of the variability on the liability scale. so, going back to this kindof study that i showed at the beginning for the twins, you can see at this point, forgwas, we can explain some fraction and depending on the cancers, it can be anywhere from 15to 50 percent of what we can see in terms of familial risks with the large number ofsnps that are available at this time. so, the shared heritability, when you start lookingat these and lining them up there are some

very interesting things that are startingto come out, where you can see very strong correlations, where there’s overlap betweencancers that you would expect, like testes, and kidneys, and cll, and large-cell b-celllymphoma, but interestingly enough, dlbcl, a type of lymphoma, osteosarcoma, share aheritability that was not anticipated. so again, this discovery element of giving usnew clues and ways of thinking about diseases is very important -- not different from howthe tcga analyses in looking at certain mutation signatures have told us things about bladdercancer and potential viral pathogens in some of the, you know, gastric cancer, and ebv.these are the kinds of things that, looking across these large sweeps, give us new placesto go.

so, lastly, really, what when we talk aboutgwas, what’s in a gwas region? we know that it can inform our understanding of the somaticchanges, particularly in that region. we have many correlated snps that have to be mappedand choose the best variance for laboratory evaluation. so, of those 475, only about 25are explained right now, and a small fraction of them may allow us to really look at environmentalor other genetic alterations. so, we have a wonderful resource that, again, nhgri wasreally the driving force of this. it really has, i think, transformed how and in whatway to prosecute these and this gives us the opportunity to be able to map and go aftereach region. so, let me just give you an example here,where there’s a potential clinical implication,

i think that mila profinina olsen [spelledphonetically] had identified with one of the bladder signals on chromosome eight, the pscagene, where she mapped it, figured out the very best snps, statistically and analyticallyin the laboratory. you can see that the functional snp changed the expression of this particulargene, and it just so happened there’s a humanized antibody to this particular genebeing tested in other cancers, and so, we’ve been trying unsuccessfully, but still pushinghard to ask the question, is this the disease where this particular humanized antibody shouldbe tested. and here is a potential translational application of identifying a particular biologicstory that comes out of looking at a particular gwas region. this was not to promise thatall gwas regions will look like that, but

i think there is very interesting biologyin terms of the regulation and the changes in very important pathways, in particulargenes, that are critical for cancer. so, we come back to the architecture of geneticsusceptibility of cancer and this sort of middle space here of the low-frequencies thathave the intermediate effects. and, actually, jeff trent was central to one of the examplesi’m going to show in a minute that kevin brown, who we hired from jeff as an intramuralinvestigator, was able to do this. and it’s very important that the laboratory activityis there, because it really does help us get past the signal-to-noise ratio. for thosethat have looked at exome sequencing and seeing 5,000, 2,000, 10,000 interesting-looking variants,it’s very hard to know which ones are the

right ones and to do the agnostic search forrare variants is very difficult, as eric lander and others have suggested, that we’re goingto need 20, 30 thousand cases just to begin to identify, and get the right signals tocome out of this, and, you know, this gets at some very profound questions. so, kevin looked at the mitf gene, the e31akmutation, that had no perfectly segregated in families with melanoma, nor was it thatstrong of an effect in the population, but it was clearly there. but the interestingthing was when they when in for the laboratory, as did a group in france in parallel, [cough]they published -- excuse me -- in “nature,” this very interesting study where they -- therewas a lot of biology of assimilation [spelled

phonetically] of that particular moiety onthe mitf gene, sort of giving the scientific laboratory corroboration that this is an importantrisk factor. similarly, we’ve gone ahead, and so, terry landi and jianxin shi in ourprogram, looking at pot1, and important gene in telomeres’ stability, identified verysimilarly. families in populations where the effects were not segregating like our classicalmendelian families, and they weren’t quite strong enough, as we saw in the genome-wideassociation studies, but they had singles in both, that when we went to the laboratory,were able to identify very important laboratory experiments that really sealed the deal, soto speak. and i’m afraid that this space is going to be one that is very difficult,it’s going to be much slower to get to,

where we’re going to have to use laboratoryevaluation as well as statistical operations to be able to get there. so, we know thatthere are many difficult regions to get at, and we won’t necessarily get to all of them,and the low region here individually, but the polygenic models of snps will allow usto get that, and then we have, occasionally, these very rare things. so, i think at this point, the report cardon cancer genomics in 2015 is that it’s really just the start. we really have a waysto go. and it’s been a very exciting discovery period, but it should not end. the battleis clearly not over. we know that discovery is in progress and we’re defining very differentstructures for the underlying genetic architecture.

we know that the current profiles are bettersuited for risk stratification, a form of precision prevention, but we haven’t figuredout how to develop those studies yet to confirm those. and then the discovery of new biologicinsights into cancer are clearly very important but the next real frontier, i think, is toget to the environment and molecular heterogeneity. so with that, i’d like to acknowledge -- i’mgoing to go on for about five more minutes, dan, because i want to talk about how thegenome is falling apart, but i wanted to identify and particularly call out the remarkable colleaguesthat i’ve had the pleasure of working with, particularly, joe fraumeni and bob hoover,and peggy tucker, and certainly a number of other individuals within dcg, and, you know,the slides would go on like a hollywood movie

for three minutes of music if i were to showthe 400 collaborators, and all of their associations, but this is really the value of team sciencein a really very special way. so, let me just say a word or two about genome screening,you know -- is it promising? is it haunting? is it dangerous? it’s probably some of each, at this point.and, you know, as we go forward with next-generation sequencing of tumors that means we are sequencingnormal tissue, and it’s a very hard issue ethically to how not to look at that information.and when we start looking at that information, we ask very important questions about what’sgoing on with our genome. are we going to have to sequence our genome more than once?and, i would say, we may be faced with having

to make those decisions, because i would sayaging is tough. it really is. we fall apart with arthritis, obesity, heart disease, cognitivechanges, we have decreased oxygen consumption, immunosenescence, fewer neurons, telomereattrition, genetic mosaicism. and so, one of the things that we’ve noticed, as wewere doing six years of gwas, we looked at over 100,000 samples in 45 different populationstudies. we kept seeing these, sort of funky q.c. failures, but we saw enough of them thata couple of these astute people in the laboratory said, “hm, [spelled phonetically], theremay be something there.” so, what we unexpectedly found was that largechromosomal abnormalities. so, about one and a half to two percent of the population overthe age 50 is walking around with a sub-population

of cells in their blood or their buckle componentthat are these very ugly-looking mosaic events. and i think this is something that sort oftriggered this whole world of asking the question of the dynamic genome. and we know that wecan see this in many different populations. we’ve extended this now to over 125,000individuals, and we know that the phenotypic expression of mosaicism has certainly beenaround. classical genetics told us about eye disease, you know, calico cats, neurofibromatosis,and the like, and we know in the extreme it’s an age-old explanation for a subset of neurofibromatosisand trisomy 21s, and turner’s. we know that it’s also very important for rare, highly-penetrantmutations that lead to variegated aneuploidy, that tell us a lot about stability of chromosomes,the bub1b families, and the set57 families,

as rare as they are. and we also know that,you know, the complex syndromes, where we see -- and some of the leading investigatorsat nhgri have identified some of these very perplexing situations where what we wouldsay in the cancer world, an akt1 mutation of lung cancer or neuroblastoma, you see inthe germ line, that is expressed only in a particular tissue, you know, giving rise toproteus syndrome or ollier’s disease. it’s really quite striking. so, we clearly know about this, but when westart looking at the large -- here is the chromosome, you know, the homunculus chromosomeof 122 of the autosomes, and, if we look at 127,000 individuals, this is a paper thatmitch has led that will be published very

shortly, we can see that there are differentkinds of events that are gains, or copy-neutral, or losses, in very large-scale. and we knowthat this is really the tip of the iceberg, and we know, unfortunately, that this increaseswith aging. so, if we look at all of our cohorts from age 50 to 75 these events increase insize. and the question is, are they harbingers of neurodegenerative, diabetes, cancer, andthe like, and this is really a very difficult question. we don’t have evidence at thispoint that there are strong risk factors for developing cancer, per se. there’s somepapers looking at complications of cardiovascular diabetes disease, but, again, this is stillthe start of it. if we look at bichromosomes, we can see that the x chromosome was hit veryhard, interestingly enough, and the y has

the most number of mosaicisms. so for men,15 to 20 percent of the men at age 60 are missing a good part of their y chromosomes,which is very interesting -- i’ll show you data on that. but here, it’s why the x chromosomeis very interesting, and then there are these regions on chromosome 13 and 20 that are veryimportant in the hematologic cancers, that you see normal individuals walking aroundwith those. so, the hypermutation of the inactive x is very a very active field in the somaticworld. so, it’s telling us something about the replication of the inactive x being thelast chromosome to be replicated, that there’s more error that takes place in the icgc andthe tcga data. and so, we’re asking this question, could this be restricted to theinactive x, and we’re not sure, but we’re

moving forward on that right now. there have been a couple of papers lookingat y loss as causal or consequence of aging and smoking. the swedish group has suggestedthat it’s important to susceptibility to cancer, and have actually started a company,you know, i mean, you may as well flush your money down the toilet the best we can tellbecause they data is not very strong. when we look at our large cohorts we see absolutelyno effect for susceptibility, but we do see age. and here, you can see, by the time peopleare in their 60s to late-70s, 20 percent of the men have lost almost all, or all of theiry chromosome, and their mosaic thereof, and so it’s really important. similarly, thesurvival analysis has been suggested, but

we don’t see any effect whatsoever whenwe look in our large cohorts that we followed for a number of years, and the probabilityof an event decreases, interestingly enough, if you stop smoking, you have less risk ofhaving that y chromosome mosaicism. so, in our minds, this is sort of the tip of theiceberg, looking at these large-scale events. and a number of other groups have startedto look at this with sequencing, looking at favored hematologic genes. there are age-relatedmutations that are associated with clonal hematopoietic expansion and malignancies,looking at the tcga data, age-related clonal hematopoiesis, again, of looking at individualsequence-based changes seen to populations of cells.

so, to take a step back, the hematologic cancersare very different, in our mind, and we’ve looked very closely in our scanning, in ourcohorts, and are able to see -- as well as did the geneva -- that there’s an increaseof the number of these kinds of events that are seen particularly in individuals who goon and later develop a cancer. so, in other words, is this a potential biomarker? couldthis be exploited to screen people who might be at high risk? but, we don’t know whatall those risk factors are but we certainly can look and see, you know, untreated leukemias,particularly have an increased risk of having one of the events of 13 or 20 per se. so,when we looked at the cll gwas that we did, and we particularly looked at individualswho had blood anywhere from two to ten years

or more before their diagnosis in these prospectivecohorts, we can identify a series of mutations that were seen in mosaic states in these individualsas long as 14 years before their actual frank diagnosis of cll. we don’t have the full,you know, the full karyotyping of all of the events, but we can see that they are all eventsthat are reported in cll. the reds are those that are of poor prognosis. so, it does raisethis question, of being able to see well, you know, as much as 10, 12 years in advanceof a diagnosis, the cll that somebody could have one or more clones that are identifiedat a high-enough fraction that could be detected by our current technologies, which is aboutfive percent of the circulatory cells. we can -- that’s our discriminatory difference.

so, our implications for aging, really, inour minds, are very important in thinking about this sort of global concept of genomicinstability that has been described by others, and it gives us clues to what can be tolerated,or potentially selected in cancer. and as we go forward in thinking about precisionprevention, i think this notion of mosaicism is going to be particularly important in monitoringindividuals up to a certain point. it’s are those changes specific to the cancer,or are they part of a sort of global system that’s sort of falling apart, and this isa very important hypothesis that i think large-population studies really need to look at. and we certainlyknow the role of this in non-cancer diseases that track particularly with ages, and therehave been some reports recently, and i think

we will see more and more as they come along. so, let me just end by saying, you know, tobe able to do this work, it’s really a pleasure to work with so many people -- to quote agreat princetonian president who happened to then move to the white house, woodrow wilson,you know, but to paraphrase, we use not only all the brains we have but all that we canborrow, and in doing that, for instance with the mosaicism, we have these huge consortiumswith hundreds of individuals. and, again, these are the kinds of things that are criticalto be able to make these large, population-based observations. it’s going to drive us backto the laboratory and make us think hard about the next public health questions, and wherewe want to implement these particular observations.

so with that, i will stop, and thank you again,and i very much appreciate the honor of giving the trent lecture. thank you. daniel katsner:well, stephen, thank you very, very much for that spectacular lecture, and, limited aswe are in terms of the kinds of gifts that we can bear, at least publicly, i have thissmall token of our appreciation for the national human genome research institute that commemoratesthis wonderful lecture. all right, and i think we have a little bitof time for some questions, and, of course, there is a wonderful spread of food out inthe library awaiting us after the last question is asked. so, anyways --

male speaker 1:just two brief questions. as a pathologist, i’ve seen problems with prostate and breast.in particular, prostate is a natural occurrence in older males -- steve chanock:right. male speaker 1:-- and, in -- all through the spectrum when you find a low gleason-grade prostate carcinoma,or what appears to be one, you don’t know if it really is something that is just goingto be there for the guy’s life or what’s going to go on. so i suggest to you that thedefinition of what is a prostate carcinoma is important in terms of biological behavior.and the second thing is, in terms of breast,

you get what’s called an atypical ductalhyperplasia and nobody knows what it is. is it going to become cancer, or isn’t it?i understand your markers, but if a pathologist is going to start calling them when they getto a certain point of atypia, “this is a cancer,” it’s not going to be helpfulin terms of you defining cancer risk. so, i think definitions by pathologists, in termsof those two cancers specifically, are needed before you can move forward in defining cancerrisk. you have to define which biologically or which -- what is your definition of a cancerfor prostate, and what is your definition for breast cancer versus atypical ductal hyperplasia? steve chanock:well, thank you. your point is very well taken,

and i would like to assure you that thereis a tremendous amount of effort focused on this. so, in a number of the scans that havebeen done, both in breast and prostate, the question -- the issue of limiting them toindividuals that have particular states of gleason, seven and above, and a tremendousamount of effort has gone into trying to standardize in a lot of the international studies. this has been one of the challenges. what’svery interesting about prostate cancer is, when you look at the regions that you findfrom scanning or analyzing seven or even eight and above, and then you bring back in thefive -- the rare fives and the six, you see, basically, the same regions are lighting up.and this has been a big disappointment. this

has been a hard thing, the idea of are theregenetic determinates or genetic factors that contribute to the risk of having very aggressivetypes of prostate cancer. we have been very hard-pressed to find them. we have one ortwo that we are just putting to press and another group has one or two that has withstoodthe test of time of being replicated over a number of studies, that spend a lot of timegoing through this issue of pathologic review and pathologic, sort of, transmissibilityfrom one study to the next. for breast cancer, the breast cancer consortiumhave been very careful in trying to separate out the early legions from what -- in cytofrom what would be considered to be frank carcinoma. and a number of the studies arenow moving on using molecular characterization

of saying, you know, luminal a, luminal b,triple negatives, part two, end up in those types of molecularly-defined types, to beable to more -- to better refine the analyses and to be sure that we are looking at comparablethings, because, a disease like breast cancer may be as many as nine or 10 different typesof breast cancers. and so, i think as we accumulate these very large studies we do have opportunitiesto look at the sub-type specific effects and how they are, but i think, you know, thisepidemiologic world works very closely with, you know, scores or hundreds of pathologistsworldwide to address these questions. male speaker 1:and just one brief comment, your aging hypothesis has been given credibility by another pathologisthere who gave a lecture last week, saying

that the bcl2 is known to be elevated withage. male speaker 1:bcl2 being the, what is it, bcl lymphoma gene that is known to cause immortality in cells,and antiapoptotic. thank you very much. steve chanock:thank you, sir. thank you. male speaker 2:so, what is about the y chromosome, and why is it disappearing faster? steve chanock:good. my wife’s here -- you can ask her [laughs].well, the y chromosome is -- there are two aspects that are very interesting about it.one is, if you actually look at the topography

of the y, there’s a lot -- you know, there’sthe pseudoautosomal, and shared with x chromosome. so, the amount of real estate that we considerto be unique is a much smaller amount that we’re looking at, and, you know, there arerelatively fewer genes that are involved in things other than sex determination and fertilitythat are on the y chromosome. so, you know, there is a lot of hand waving but i don’tthink anybody have a very concrete definition of, you know, gc content, or something aboutthe actual structure of where those breaks would take place. you know, it is a remarkablephenomena that that’s tenfold more common in men than you see in women. remember i showedyou that the women had higher rates of these larger events, but again, that’s still downin the weeds compared to where the men are.

male speaker 2:so, what happens to the function of the people that are most, i guess losing most of it,most of the y chromosome? steve chanock:well, many of them go on, and may be president of the united states, or do whatever. i mean, it’s a high enough fraction. ifwe look at the plco, for instance, a cohort where there are a lot of very-high-performingindividuals, we haven’t done the mapping against their professional and their personaloutcomes, and i wouldn’t want to care to do that, but it is, you know, an interestingevolutionary question, at what point does the y chromosome become less important biologicallyand i think the mosaicism certainly does press

that question. male speaker 2:thank you. good luck in exploring. daniel katsner:all right. well, i think we probably ought to call it to a close, and please do joinus for the reception over in the nih library, sponsored by our friends at the faes. thankyou very much for coming. [unintelligible dialog] [end of transcript]